CN116602771A

CN116602771A - Three-dimensional robot biological printer

Info

Publication number: CN116602771A
Application number: CN202310672384.0A
Authority: CN
Inventors: M·肖汉姆
Original assignee: Mazor Robotics Ltd
Current assignee: Mazor Robotics Ltd
Priority date: 2017-04-02
Filing date: 2018-04-02
Publication date: 2023-08-18
Also published as: CN110769771A; US20210007778A1; US11864795B2; EP4000551A1; WO2018185755A1; KR20200002879A; EP3606461B1; JP2020515372A; EP3606461A1; EP3606461A4; AU2018248134A1; CN110769771B; US20240156492A1; KR102493255B1

Abstract

The present disclosure relates to three-dimensional robotic bioprinter. A minimally invasive system that uses a surgical robot as a three-dimensional printer for manufacturing biological tissue in a subject. Preoperative planning is used to both instruct and control the motion of the robot and robotic bio-ink extrusion. The robot motion is coordinated with the ink extrusion to form layers of desired thickness and size, and the use of different types of ink enables the composite element to be laid. Such systems have a small diameter bio-ink ejection mechanism, typically in the form of a piston driven cannula, that enables access to areas with limited space (such as joints). The robotic control is programmed to make an angular movement about a pivot point at an insertion point into the subject. The bio-ink may be stored in a predetermined layer in the cannula to enable sequential dispensing from one cannula.

Description

Three-dimensional robot biological printer

The application is a divisional application of an application patent application with the international application date of 2018/4/2, the international application number of PCT/IL2018/050384 and the application number of 201880036057.3 entering the China national stage, and the problem of 'three-dimensional robot biological printer'.

Technical Field

The present invention relates to the field of bioprinting, and more particularly to bioprinting performed in vivo using minimally invasive robotic surgical (surgical) systems.

Background

Tissue engineering using three-dimensional bioprinting has been a promising area of research, providing promise for bridging the gap between organ shortage and transplant demand. Three-dimensional bioprinting allows tissues or potentially even organs to be engineered (engineer) and subsequently implanted into a subject, thereby greatly reducing the time for a patient to wait for treatment. Furthermore, the use of this possibility may avoid rejection of the implant and the need for anti-rejection drugs, since the tissue may be engineered from a small amount of subject tissue (autologous tissue).

An overview of three-dimensional printing of organs can be found in the article by Rengier F et al entitled "3D printing based on imaging data:review of medical applications (3D printing based on imaging data: review of medical applications)", published in International Journal of Computer Assisted Radiology Surgery (journal of international computer-aided radiosurgery), month 7 of 2010; 5 (4) 335-41.Doi:10.1007/s11548-010-0476-x. Electronic publication 2010, 5 months, 15 days.

U.S. Pat. No. 7,051,654 to Boland et al, "Ink-Jet Printing of Viable Cells (Ink jet printing of living cells)" describes a method for forming an array of living cells in a human-like environment by Ink-jet printing a cell composition comprising cells onto a substrate wherein at least about 25% of the cells remain viable on the substrate after 24 hours of culture. However, this prior art describes only the biological printing of living cells onto a substrate, and does not describe printing directly into the body of a subject.

The paper by xiaoeng Cui et al entitled "Direct Human Cartilage Repair Using Three-Dimensional Bioprinting Technology (direct human cartilage repair using three-dimensional bioprinting techniques)" states that this 3D thermal inkjet based bioprinting/photopolymerization method provides a first example of a computer controlled layer-by-layer build material with sufficient mechanical stability for cartilage development ", published in Tissue Engineering (tissue engineering): part a, volume 18, numbers 11 and 12, 2012. This reference describes printing in vitro onto bio-paper using 50 nozzles in each printhead using a modified HP Deskjet 500 printer, and then checking cell viability 24 hours after printing.

In addition to methods of engineering living cells, methods and systems for engineering autologous or non-autologous tissues and organs in vitro and subsequently implanting them into the body of a subject are also described. However, such methods require openings of the same order of size (order) as the final size of the printed tissue, greatly increasing trauma to surrounding healthy tissue.

For example, the paper titled "3D bioprinting and its in vivo applications (3D bioprinting and its use in vivo)" published by the university of sambac bioengineering technology and bioengineering institute bioengineering system, by Nhayoung Hong et al, in the korean water company describes a bone tissue structure which is "cultured in an osteogenic medium (medium) for one week" and then subcutaneously implanted into a mouse with immunodeficiency. Furthermore, the article states that "there are still problems to be solved" vascularization of … … tissue, such as cell viability and vascularization of printed tissue to be composed into larger and more multifunctional tissue or organ, is a major limiting factor in manufacturing human-grade tissue, and thus in vivo printing is limited to small dimensions (several millimeters) with clinical relevance that enable nutrient diffusion. The article further states that "one of the important drawbacks of wrapping living cells in biological material is that the cell-biological material suspension needs to be kept in the material reservoir for a considerable period of time; this compromises cell viability and limits their biological activity. Thus, there is a need for a more automated way … … "of loading and spraying cell-biomaterial suspensions"

Currently available methods and systems for direct bioprinting into a subject (typically developed for cartilage repair, which avoids such vascularization problems) require printheads with large-sized elements and require incisions on the same order of size as the printheads. Some prior art systems also require invasive insertion of a sensing device, such as an endoscopic camera. Chinese patent application CN 104688388 entitled "3D (three-dimensional) printing technique-based cartilage repair system and method (cartilage repair system and method based on 3D (three-dimensional) printing technology)" shows in fig. 1 as well as fig. 2, 3D a scanner 5 and a camera 6 positioned on the nozzle bar 2, both the scanner 5 and the camera 6 increasing the diameter of the nozzle bar, except for a turbocharger 22 which actually protrudes from the nozzle bar and further increases the size of the insertable part of the device. A further disadvantage of this system is that the nozzle stem is rotated by a mechanical radial rotation mechanism 4 disposed entirely within the anatomical knee joint cavity. This would appear to substantially increase trauma to the subject tissue and reduce the volume that the nozzle can print, potentially requiring multiple insertions to achieve the desired volume.

Chinese patent application CN 204092271 discloses a tube for bioprinting in a subject. This reference shows that in fig. 2, the first tube body 10 includes a print tube 20, a detection tube 30, and an illumination tube 40, all of which increase the diameter of the first tube body 10. Fig. 1 of the reference shows an image data output port 302 at the distal end of the tube that increases in size at the distal end. The device further requires a lead for proper positioning of the device within the body. Since the device is a flexible tube, movement of the tube is complex and requires imaging elements for real-time position analysis. Such complex movements may also increase trauma to the tissue.

In Di Bella C et al, entitled "In situ handheld three-dimensional bioprinting for cartilage regeneration (in situ hand-held three-dimensional bioprinting of cartilage regeneration)", a "hand-held 3D printing device (bio-pen) is described that allows direct simultaneous co-axial extrusion of a bioscaffold and cultured cells into cartilage defects in a single surgical procedure in vivo", published in Journal of Tissue Engineering for Regenerative Medicine (J. Tissue engineering for regenerative medicine) at 5 months 17 in 2017. However, the stylus is hand-held such that the accuracy of its positioning depends on the dexterity of the surgeon. This disadvantage is particularly evident in cases where the trajectory required to construct a three-dimensional biological object is complex. Furthermore, if the trajectory of the stylus during the surgical procedure (procedure) is at the discretion of the surgeon, the surgeon may choose an inefficient path or a path that results in poor results.

Another major disadvantage of most modern bio-pens is that such devices are often so large that a large opening in the subject is required, even requiring for example the opening of a knee joint. This is due to the fact that: if more than one type of tissue is to be printed, the bio-pen needs to carry (host) at least two cartridges, chambers or compartments of different bio-ink types, and this increases the diameter of the device when the cartridges are positioned within the insertable portion of the bio-pen. For example, cathal D O' Connell et al, 3/22, volume Journal Biofabrication (journal of Biomanufacture) 8, entitled "Development of the Biopen: a handheld device for surgical printing of adipose stem cells at a chondral wound site (Biopen development: hand held device for surgical printing of adipose Stem cells at cartilage wound sites)" states that "the Biopen is composed of a 3D printing chassis containing two ink chambers (labeled" left "and" right "), a 3D printing (titanium) extruder nozzle, and a UV source. The user (i.e., surgeon) may individually control the extrusion through each ink chamber via a pneumatic extrusion system. The surgeon may use a foot pedal to squeeze from the "left" or "right" chamber or simultaneously squeeze from both chambers. "in this reference, not only does the positioning of the stylus depend on the surgeon's dexterity, but the extrusion is manually controlled and thus may depend on the surgeon's pedicle (pedicular) dexterity. Furthermore, when different tissues are printed in different layers, such as in the case of cartilage structures, for example, the handheld device cannot provide the required stack of thin layers due to the lack of accuracy of the manual coating layer.

Accordingly, there is a need for systems and methods that can accurately perform minimally invasive surgery with small diameter insertable devices that overcome at least some of the disadvantages of the systems and devices shown in the prior art.

The disclosure of each of the publications mentioned in this section and in the other sections of this specification is incorporated herein by reference in its entirety.

Disclosure of Invention

The present disclosure describes new minimally invasive systems and methods for in vivo fabrication of biological tissue (e.g., for cartilage repair) within a subject's body using a surgical robot as a three-dimensional printer. These systems utilize integrated preoperative planning to accurately command and control both the movement of the robot during the surgical procedure and the extrusion of ink. The two robot functions are performed in cooperation with each other. Such systems have a small diameter bio-ink ejection mechanism, typically in the form of a cannula, and the robotic control is programmed such that angular movement applied to the cannula occurs about a rotation point at the insertion point into the subject in order to minimize trauma to the tissue and increase the printable volume, thereby reducing the need for additional incisions.

The bio-ink ejection mechanism generally includes: a cannula configured to puncture a subject; a bio-ink storage volume adapted to carry one or more bio-inks in a predetermined amount; a bio-ink extrusion mechanism, such as a robotically controlled plunger, configured to move one or more bio-inks distally (distally); and a nozzle at the distal end of the cannula, the nozzle adapted for jetting bio-ink in the subject to form at least one layer of biological material. In-vivo fabrication of printed tissue provides an optimal environment for growing printed tissue cells and an optimal incubator, as opposed to growing tissue in an incubator outside of the body.

Unlike some prior art systems that require multiple bio-ink chambers (which increase the size of the insertable portion of the device), the system of the present disclosure may optionally have only a single small diameter volume for containing one or more types of bio-ink prior to extrusion. Such a volume may be a cylindrical volume within a cannula, which may be, for example, a needle or a catheter. Since a single small diameter volume may be capable of carrying more than one different bio-ink type arranged in layers along the length of the storage volume for sequential extrusion, the diameter of the insertable portion of the device may be limited only by the size of the nozzle, which should be large enough to provide a sufficient amount and width of ink extrusion. Alternatively, several supply tubes may be connected to a single printhead, each supply tube having a different cell type, similar to some arrangements used in color printheads.

Furthermore, unlike some prior art systems in which both the positioning of the device and the bio-ink extrusion are manually controlled, in the presently described system both can be conveniently robotically controlled, thereby increasing accuracy. A surgical plan may be preoperatively determined, the surgical plan including at least one of a predetermined (i) shape, (ii) composition, (iii) location, and (iv) size of the three-dimensional tissue element. Because the preoperative planning is comprehensive, it is known in advance which bioinks will be needed, as well as the order and amount of bioinks needed. Thus, it is possible to prepare different biological materials advantageously provided in gel form in pre-calculated layers, in the storage volume of the cannula, in the correct order and quantity, according to the surgical plan, before surgery, thus requiring only a single extrusion device volume and thus reducing the diameter of the inserted device. This approach greatly reduces trauma to healthy tissue surrounding the target 3D printed area.

The surgical plan may be input to a controller that analyzes the desired 3D printable volume and determines the corresponding desired movement of the bio-ink jetting mechanism in multiple degrees of freedom during the surgical procedure. The movement of the robot should be instructed by the controller so that the cannula of the bio-ink ejection mechanism follows a predetermined trajectory. The controller may also use analysis of the surgical plan to determine the type of ink required to be ejected from the nozzles and the sequence, amount, and rate of ejection of these bio-inks.

In addition to instructing the surgical robot to manipulate the position and orientation of the bio-extrusion mechanism at the surgical site and cooperatively controlling the ejection of bio-ink to form the three-dimensional tissue element according to the pre-operative surgical plan, the controller may be further configured to provide a requirement for filling the cannula with one or more bio-inks prior to the surgical procedure according to the pre-operative surgical plan. The requirements should include the amount and type of bio-ink required and, if only a single cylindrical volume is provided, the requirements should also include the order and volume of the layers of bio-ink required in the cylindrical volume ink delivery system. The controller executes instructions and process steps by way of hardware components, such as a computer or microprocessor. The controller may further comprise a memory component for storing information.

Because some prior art systems require an invasively inserted imaging device in order to enable the surgeon to see the location and progress of the printing procedure, an adverse contribution is made to the diameter of the insertable portion of the device. In contrast to such systems, the registration process may be used to match the spatial coordinates of the preoperative plan to the coordinate system of the robot and the coordinate system of the subject area to which the bio-ink was printed during the intraoperative 3D manufacturing. This eliminates the need for an endoscopic camera or any other imaging device on the bio-ink ejection mechanism itself configured for insertion into a subject. The registration process may be performed by matching the preoperative image with the intra-operative image or, alternatively, by using a navigation tracking system to perform real-time tracking of fiducial features as well as the robot. Through the use of such a registration procedure, the robotic bioprinting system may operate without any imaging, sensing, or illumination elements, such that the diameter of the insertable portion of the device may be limited to the required cannula diameter and nozzle opening size for providing sufficient bio-ink flow, regardless of whether the cannula is simply a flow cannula with a reservoir of bio-ink positioned proximal of the cannula, or a composite cannula that also contains a bio-ink storage volume.

A further feature of the presently disclosed system is that movement of the nozzle in multiple degrees of freedom may be advantageously performed about a single pivot point or fulcrum located at the insertion point of the device into the subject. The terms "fulcrum" and "pivot point" may be equivalently used throughout this disclosure. In addition to any relative angular positioning about the insertion point, the cannula may also be longitudinally movable through the insertion point. This increases the printable volume while reducing trauma to the subject tissue. Since the bio-ink ejection mechanism may comprise multiple bio-ink types, the multi-DOF bio-ink ejection mechanism may extrude multiple materials on the same horizontal plane and/or different materials on different horizontal planes. For example, printing of the disc (including annulus fibrosus at the circumference and nucleus pulposus at the center) may be made possible by: the type of bio-ink printed alternately according to the position of the robot equipped with nozzles allows to deposit two different materials at the correct position, thus creating the annulus and nucleus of the intervertebral disc.

In the systems and methods described above, the term "three-dimensional bioprinting" is used to describe a process for laying down (lay down) layers that will generate in-vivo elements. This process may take a number of different forms, including both: a true inkjet-type mechanism in which droplets of bio-ink are ejected by heating the bio-ink at the head or by application of a high intensity acoustic field (either of which would generate tiny bubbles, forcing an equivalent volume of bio-ink out); and extrusion type printheads that utilize a syringe with a plunger or applied air pressure that forces a biologic ink drop out of a tiny nozzle. Other types of microprinting are also available. It is to be understood that throughout this disclosure and as set forth in the claims, the terms "three-dimensional printing," "inkjet extrusion," or "jetting," and similar terms are intended to include any such method of three-dimensional generation of elements by laying down successive layers, regardless of the particular type of three-dimensional printhead used.

Thus, according to an exemplary implementation of the apparatus described in the present disclosure, there is provided a system for forming a three-dimensional tissue element in a subject according to a preoperative surgical plan based on at least a three-dimensional preoperative image set, the system comprising:

(i) A cannula configured for insertion into a subject through a surface opening having a lateral (lateral) dimension on the same order as a lateral dimension of the cannula, the cannula configured for attachment to a surgical robot and comprising a nozzle at a distal end thereof adapted for ejecting one or more bio-inks to form at least one layer of bio-material in the subject,

(ii) At least one bio-ink extrusion mechanism configured for distally ejecting one or more bio-inks from the cannula, and

(iii) A controller adapted to:

(i) Instructing the surgical robot to adjust the longitudinal position and orientation of the cannula in the subject according to the preoperative surgical plan, and

(ii) Controlling the extrusion mechanism such that the bio-ink is ejected according to the longitudinal position and orientation of the cannula in the subject,

Wherein the system enables formation of a three-dimensional tissue element having a dimension greater than a lateral dimension of the cannula within the subject, and wherein the surgical robot is configured for performing an adjustment of the orientation of the cannula within the subject using the surface opening as a pivot point for the orientation of the cannula.

In such systems, the controller may be further adapted for obtaining registration of the coordination system of the surgical robot to the three-dimensional preoperative image set. In the case of one of these systems, the preoperative surgical plan may include at least (i) geometric forms, (ii) components, (iii) locations, and (iv) dimensions of the three-dimensional tissue elements.

According to a further implementation of such a system, the preoperative surgical plan is determined at least in part by the controller using at least one of: (i) Image processing of a three-dimensional preoperative image set and (ii) input from a surgeon. In such systems, the determination of the preoperative surgical plan may further utilize analysis of data from a medical database.

Still other implementations may include a system as described above wherein one or more bio-inks are contained in (i) a cannula or (ii) one or more bio-ink storage volumes fluidly connected to a cannula. According to option (i) of such a system, the cannula is configured for containing at least two bio-inks arranged in layers along the length of the cannula, the layers having predetermined amounts, compositions and order. In this case, the predetermined amounts, composition, and order of layers may be determined by the controller according to the preoperative surgical plan.

According to yet further implementations of such systems, the entirety of the three-dimensional tissue element may be formed without the need to remove the cannula from the subject. Such three-dimensional tissue elements are formed by: (a) Performing an adjustment of the orientation of the cannula at a first depth in conjunction with the incremental longitudinal movement of the cannula to form a first layer of biological material, and (b) subsequently moving the cannula to a second depth within the subject, and performing an adjustment of the orientation of the cannula at the second depth in conjunction with the incremental longitudinal movement of the cannula to form a second layer of biological material, and repeating (b) until a three-dimensional tissue element is formed.

In any of the systems described above, the surface opening may be utilized to provide access to the subject's knee. Further, the bio-ink extrusion mechanism may be any one of a piston, an external pressure application device, a pneumatic device, or a bio-ink jet print head. Furthermore, the diameter of the cannula may be less than 3mm or even less than 3mm.

According to yet a further implementation of the system described above, at least one of the layers of biological material may comprise cartilage, bone medium, muscle, vascular or ligament material.

Still other implementations of such a system may further include at least one three-dimensional tracking target associated with the surgical robot, and wherein the controller is adapted for registering the coordination system of the surgical robot to the three-dimensional preoperative image set using the at least one three-dimensional tracking target. In such cases, the system should further comprise a reference marker or a fluoroscopic imaged anatomical element, the reference marker being disposed on at least one anatomical element of the subject, and wherein the controller is further adapted for using the at least one three-dimensional tracking target to register the coordination system of the surgical robot to the reference marker or to the fluoroscopic imaged anatomical element. In such cases, the controller may be further adapted for creating a pseudo-three-dimensional image comprising the coordination system of the surgical robot with respect to the anatomical reference marker or with respect to the fluoroscopically imaged anatomical element; and for associating the selected window of the pseudo three-dimensional image with a similar selected window of the three-dimensional preoperative image set such that the position of the surgical robot may be registered using the preoperative surgical plan.

Any of the systems described above may further comprise a steering mechanism for steering the nozzle of the cannula in a desired direction. Furthermore, the cannula may include at least one controlled link or joint (joint) such that the nozzle has increased accessibility.

Further implementations according to the present disclosure further provide methods for determining a surgical plan for a surgical robot.

A method for determining a surgical plan for a surgical robot utilizing a cannula inserted into a subject by the surgical robot through a surface opening, the cannula including at least one nozzle at a distal end thereof adapted for ejecting one or more biological inks to form at least one layer of biological material in the subject, the method comprising:

(i) A three-dimensional preoperative image set of the subject is obtained,

(ii) Determining a preoperative surgical plan based on at least the set of three-dimensional preoperative images, the preoperative surgical plan including at least (a) shape, (b) component, (c) position, and (d) size of the three-dimensional tissue element to be formed by the surgical robot,

(iii) Calculating a planned trajectory of the at least one nozzle based on the preoperative surgical plan,

(iv) When at least one nozzle passes through the planned trajectory, generating a plan for the ejection of one or more biological inks for forming at least one layer of biological material in the subject according to the preoperative surgical plan, and (v) inputting the planned trajectory to a controller adapted for manipulating the surgical robot and controlling the ejection of one or more biological inks such that the nozzle can cooperate with the planned for the ejection to pass through the planned trajectory, thereby enabling the autonomous formation of a three-dimensional tissue element in the subject by the surgical robot.

Such methods may further include the step of determining a planned motion of the surgical robot from the planned trajectory. Further, the planned movement of the surgical robot may be any angular movement of the cannula required to cause the nozzle to perform the trajectory through using the surface opening of the subject as a pivot point.

Furthermore, in any of the above-mentioned methods, the viscosity of the one or more bio-inks may be such that the at least two bio-inks may be disposed in a longitudinally disposed layer within the cannula without mixing the at least two bio-inks.

According to a further implementation of the method described above, determining the preoperative surgical plan may include accessing a medical database comprising a plurality of three-dimensional image sets of the subject. In such cases, determining the pre-operative surgical plan may be performed by analyzing data from the medical database to determine the surgical plan with the highest statistical likelihood of positive results. Further, in any of these methods, at least one of the planned trajectory and the plan for ejection may be calculated using artificial intelligence.

Further, the planned trajectory may be calculated by taking into account at least one of: (i) avoiding forbidden areas that would be damaged by the cannula; (ii) a shortest track for forming a three-dimensional tissue element; and (iii) a trajectory that will cause minimal trauma to healthy tissue of the subject.

There is further provided in accordance with yet other aspects of the present disclosure a method for configuring a surgical robotic system to form a three-dimensional tissue element in a subject, the surgical robotic system utilizing a cannula inserted through a surface opening, the cannula configured for jetting at least two biological inks in the subject through a nozzle, the method comprising:

(i) A three-dimensional preoperative image set of the subject is obtained,

(ii) Determining a surgical plan from the set of three-dimensional preoperative images, the surgical plan including at least (a) shape, (b) component, (c) position, and (d) size of the three-dimensional tissue element,

(iii) Determining a planned trajectory of the nozzle according to the surgical plan, and (iv) providing a plan for the ejection of at least two bio-inks as the nozzle passes through the planned trajectory according to the surgical plan,

wherein at least two bio-inks are layered prior to jetting and the amount, location and composition of each layer of bio-inks is selected according to the planned trajectory and the jetting plan such that a three-dimensional tissue element can be autonomously formed by the surgical robot.

In such methods, the layers of at least two bio-inks may be contained longitudinally along the length of the cannula, and the layers may have predetermined amounts, compositions, and sequences. Alternatively, in such methods, each layer of at least two bio-inks may be longitudinally contained in a storage volume that is fluidly connected to the cannula. In the latter case too, the layers may be arranged longitudinally along the length of the storage volume and have predetermined amounts, compositions and sequences.

Finally, there is provided a method for performing a manual instruction surgical procedure for generating a three-dimensional tissue element in a subject, comprising:

(1) Providing a cannula comprising at least one nozzle at a distal end thereof, the at least one nozzle adapted for ejecting one or more bio-inks to form at least one layer of bio-material in a subject, (ii) inserting the cannula into the subject through the surface opening, and (iii) manipulating the cannula such that the nozzle follows a trajectory suitable for generating the at least one layer of bio-material in the subject, and ejecting the one or more bio-inks in coordination with movement of the nozzle,

wherein the manipulation is performed using an externally arranged imaging system to verify that at least the nozzle is following a trajectory suitable for generating the at least one layer of biological material.

Drawings

The invention will be more fully understood and appreciated from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. 1 illustrates an exemplary robotic surgical system for three-dimensional bioprinting in a subject;

FIGS. 2A and 2B illustrate an exemplary alternative bio-ink ejection mechanism of the surgical system of FIG. 1;

3A-3D are schematic diagrams illustrating exemplary motion patterns of a laterally inserted robotically controlled cannula according to FIG. 1 using an insertion point of a subject as a fulcrum to form layers of bio-ink;

FIGS. 4A-4D are schematic diagrams illustrating exemplary motion patterns of a vertically inserted robotically controlled cannula according to FIG. 1 using the subject's insertion point as a fulcrum to form layers of bio-ink;

FIG. 5 illustrates an exemplary application of the presently disclosed robotic surgical system used to form three-dimensional cartilage elements within a patient's knee;

fig. 6A and 6B illustrate a schematic overview of an exemplary controller configuration of the presently disclosed robotic surgical system and inputs and outputs therefrom; fig. 6A shows a simple configuration, and fig. 6B shows a more complex configuration;

FIG. 7 illustrates an exemplary method of planning a robotic 3D bioprinting surgical procedure using a controller; and is also provided with

Fig. 8 illustrates an exemplary method of performing a robotic 3D bioprinting surgical procedure using a controller.

Detailed Description

Referring first to fig. 1, an exemplary schematic surgical system for robotic 3D bioprinting in a subject is shown. The system comprises: a surgical robot 1, the surgical robot 1 being configured for 3D in vivo bio-printing; and a controller 21, the controller 21 being configured to both instruct the pose of the surgical robot and control the ejection of the bio-ink according to the pose of the robot, such as to form the three-dimensional tissue element 10 in the subject. The robotic system may operate autonomously in accordance with a preoperative surgical plan. The surgical robot is mounted on the base 20 and is adapted to clamp its end effector, which is a component for robotically controlled ejection of biological ink.

The bio-ink jetting assembly includes a small diameter cannula 12 adapted for minimally invasive insertion into a subject. In fig. 1, the cannula is shown inserted through an incision 11 in the skin 22 of the subject. The cannula may be equipped with a plunger 15 for ejecting one or more layers of bio-ink through the cannula, out of the nozzle 2 at the distal end of the cannula, and into the tissue of the subject. Although the nozzle 2 of the cannula is simply shown as a hole at the distal end of the cannula, it may be provided in the form of a hinged nozzle according to other implementations, which may be oriented over a range of angles to provide ink ejection in multiple directions without the need to move the cannula. While piston ejection is shown in the implementation shown in fig. 1, it is to be understood that alternative robotically controlled bio-ink extrusion mechanisms may be utilized, such as pressure application devices located outside the cannula, devices that release (exude) air pressure, mechanical extrusion of flexible wall bio-ink storage volumes, thermally or acoustically driven ink jets, or any other mechanism capable of extruding the desired amount of bio-ink in an accurate and controlled manner.

In fig. 1, the cannula is shown with a fine needle portion for injecting the bio-ink into the patient's tissue, and a larger diameter barrel for holding the bio-ink to be injected into the tissue. However, alternative implementations may be used in which the bio-ink injector cylinder is sufficiently narrow so that the entire cylinder may be inserted into patient tissue. The bio-ink extrusion mechanism is configured for moving one or more bio-inks distally towards a nozzle at a distal end of the cannula, the bio-ink extrusion mechanism being adapted for controlling ejection of the bio-inks to form one or more layers of bio-material. The extrusion mechanism should be robotically controlled so that the flow rate and/or amount of extrusion can be accurately metered (meter) and commanded according to the preoperative surgical plan and subsequent movement of the nozzle. Alternative cannula implementations with separate bio-ink chambers (each containing a different bio-ink composition) may require more than one bio-ink extrusion mechanism so that different types of bio-inks may be extruded separately, as will be shown below in fig. 2B. To facilitate sterilization, the cannula may be removable from the surgical robot; or the cannula may be disposable.

The robot preferably has at least five degrees of freedom so that it can spatially locate the axis of the cannula and also move it along its longitudinal direction. Six or more degrees of freedom may perform this task, typically using simpler robot programming routines, and the working volume of the robot must be able to cover the required treatment area. Robots with less than five degrees of freedom can be used, but the use of additional mechanisms to maintain fixed insertion points in space is also required in the following. The surgical robot shown in the example system of fig. 1 has a robotic arm for manipulating cannula 12 with three rotational joints 16.

Whichever robotic configuration is used, it should provide sufficient movement flexibility to the end effector so that angular movement of the cannula can be performed with the insertion point 11 maintained as a fulcrum or pivot point. The movement of the cannula about the pivot point at the insertion hole has the following advantages: enabling the robot to orient the cannula at any desired angle relative to the skin surface of subject 22 without requiring the initial opening at insertion point 11 to be larger than the opening indicated by the diameter of the cannula, and without causing pressure at insertion point 11 or even causing trauma or increasing its size during the surgical procedure. Such an arrangement allows for a maximum three-dimensional printed volume covered by the cannula through a single minimally invasive incision.

Thus, the surgical robot may be manipulated to deposit biological material not only in clearly accessible tissue locations, but even also within the crevices or under overhanging (overswing) in natural tissue. The surgical robot may further comprise a deployable distraction (distraction) device for distracting tissue of a desired location of the printable volume, such distraction device may be small enough that it does not significantly increase the diameter of the cannula when the device is undeployed (e.g., during insertion). Alternatively, a conventional pulling device may be inserted into the area where the bioprinting is being performed through an additional minimally invasive incision at a location different from the location through which the bioprinting cannula has been inserted. This arrangement may be particularly useful in compact orthopedic situations and may provide more flexibility than attempting to distract bone structures through the same incision through which bioprinting was performed. To provide further maneuverability and access within the body, the cannula or the nozzle of the cannula may be equipped with a steering device, such as a tension wire actuator connected to a circumferential location at the nozzle of the cannula, so that the print head may be steered to access difficult locations in the body. The steering device may also be robotically controlled and inserted according to a surgical plan. Alternatively or additionally, a steering device may be used to facilitate changing the direction in which the printing nozzles are oriented relative to the axis of the cannula, so that greater flexibility may be obtained in the area in which printing is being performed. Additionally, links (links) and joints may be incorporated into the cannula to enable the cannula to pass through complex channels or passages. The robot may also be programmed to first prepare the area for printing by extracting tissue and bone, for example, as is typically done in the endoscopic surgical procedure of the knee joint.

Although the surgical robots are shown herein in serial form, the surgical robots may be parallel or mixed. The surgical robot may be positioned on the floor, ceiling, bed, or attached to an anatomical feature on or near which 3D bioprinting is being performed. The surgical robot may further include actuators, additional arms, hinges, and joints, as is known in the art.

Some prior art systems require an invasively inserted imaging device in order to enable the surgeon to see the location and progress of the printing procedure, thereby adversely contributing to the diameter of the insertable portion of the device. In contrast to such systems, the registration process may be used to match the spatial coordinates of the preoperative plan to the coordinate system of the robot and the coordinate system of the region of the subject to which the bio-ink was printed during the intraoperative 3D manufacturing. This eliminates the need for an endoscopic camera or any other imaging device on the bio-ink ejection mechanism itself configured for insertion into a subject. The registration process may be performed by matching the preoperative image with the intra-operative image or, alternatively, by using a navigation tracking system to perform real-time tracking of fiducial features and of the robot. Through the use of such a registration procedure, the robotic bioprinting system may operate without any imaging, sensing, or illumination elements, such that the diameter of the insertable portion of the apparatus may be limited to the required cannula diameter and nozzle opening size for providing sufficient flow of bio-ink, regardless of whether the cannula is simply a flow cannula with a reservoir of bio-ink positioned proximal of the cannula, or a composite cannula that also contains a bio-ink storage volume. However, it is to be understood that real-time imaging (such as X-ray, CT or ultrasound) performed outside the subject's body may be used to verify the position of the robotic probe or even guide the robotic probe in real-time without the need to insert any additional invasive imaging elements into the subject's body. The latter application, i.e. the provision of a real-time imaging device, such as a C-arm fluoroscopic system or an alternative imaging method, enables the implementation of higher precision handheld bioprinting to be performed. The use of such an imaging device provides real-time information of the print position and progress without the need for an imaging device such as an endoscopic camera inserted into the subject (thereby increasing the size of the cannula), as already mentioned above. The imaging device may be positioned such that it images the area where the three-dimensional bioprinting element is being formed, and should preferably be a spherical aligner (aligner ball) such that it can image the printing schedule from a number of alternative angles.

As mentioned previously, the present system uses a registration process to facilitate matching the spatial coordinates of the preoperative plan with the robot's coordinate system and the area of the subject where the bio-ink is being printed. One way to do this is by matching the preoperative three-dimensional image with the intraoperative fluoroscopic image of the area being printed. This can be advantageously performed by matching the anatomical features of the imaging region with the indication of the robot position shown in the two sets of images (and thus with the coordinates of the robot position). The robot position may alternatively be related to the region being bioprinted through the use of a navigational tracking system that performs real-time tracking of the robot and fiducial features, such as tracking elements mounted on the patient's anatomy (anatomy). Fiducial features should also appear in the preoperative three-dimensional image. Such tracking systems are utilized in the exemplary system shown in fig. 1, as illustrated by a tracking camera 19 mounted in the area where the procedure is being performed, and a reference numeral 18 mounted on the anatomy of the subject and on spatially defined components of a robotic or bio-ink injection mechanism, such as a cannula. The use of such reference marks on the subject as well as the robot eliminates the need to provide a fixed relationship between the robot position and the subject position.

Referring now to fig. 2A and 2B, an exemplary alternative bio-ink ejection mechanism of the surgical system of fig. 1 is shown. Fig. 2A illustrates an exemplary bio-ink ejection mechanism with a cylindrical cannula 12 configured for piercing a subject and a robotically controlled plunger 15. Although in its simplest form the cannula may contain a single bio-ink to be printed, the cannula of fig. 2A is shown carrying alternating layers of three types of bio-inks (bio-ink 25A, bio-ink 25B and bio-ink 25C) having different compositions, it is understood that a single type of bio-ink or any other number of bio-inks may be layered in number or combination according to the surgical plan. The layers of bio-ink may be stacked longitudinally (i.e., along the length of the cannula) within the cannula in predetermined amounts, compositions, and sequences according to the surgical plan. The desired bio-ink layer may advantageously be determined by extrapolation from the surgical plan, the planned motion profile and trajectory, and the plan for jetting coordinated with the motion plan and trajectory using the controller. The schedule of injection may, for example, define the speed of longitudinal movement of the piston through the cannula. This layered arrangement allows the layers of bio-ink to be sequentially extruded out of the nozzle 2 by the piston 15 during the surgical procedure. In order for this implementation to be effective, the bio-ink should preferably have a viscosity such that it does not mix significantly within the cannula, such as in a paste or gel form. The robotic system may further include a robotic dock (not shown) that fills the cannula preoperatively with the desired layers of bio-ink according to the requirements determined by the controller, thereby providing a high level of precision in the amount, order, and composition of the layers of bio-ink and facilitating autonomy of the robotic system. Alternatively, the layers within the cannula may be prepared manually.

Referring now to fig. 2B, an exemplary alternative bio-ink ejection mechanism of the surgical system of fig. 1 is shown. In this implementation, separate channels are provided within cannula 12 for the different bio-ink types 25A and 25B, wherein the channels have a small diameter and are in close proximity to each other to maintain the desired small diameter cannula. The cannula tapers at a distal end where a single nozzle 2 for in vivo extrusion of bio-ink is located. In this figure, although two channels are shown, it is to be understood that any number of channels may be used. Two separate robotically controlled pistons 15A and 15B are provided so that different bio-ink types 25A and 25B can be extruded separately.

In alternative implementations, one or more bio-inks or bio-inks may be carried partially or entirely outside of the cannula and may be contained in volumes of any shape, but should be fluidly connected to the interior volume of the cannula to provide a flow of bio-ink distally through the cannula. The cannula may further comprise a micro UV lamp that does not significantly increase the diameter of the insertable portion of the robot for polymerization of the bio-ink. It is to be understood that the term "cannula" as used throughout this disclosure may be a needle, catheter, or any other insertable surgical tool.

Reference is now made to fig. 3A to 3D, which are schematic drawings showing an exemplary movement pattern of a robotically controlled cannula 12, which robotically controlled cannula 12 has a nozzle 2 at its distal end according to fig. 1, using the subject's insertion point 11 as a fulcrum to form a bio-ink layer. Fig. 3A-3D illustrate an exemplary implementation in which cannula 12 is inserted laterally into a subject, such as into a knee of a subject, for the purpose of injecting a three-dimensional cartilage element, as will be shown in more detail in fig. 4. In fig. 3A, cannula 12 is minimally invasively inserted into the subject's body to a desired depth through incision 11 in the skin of subject 22 specified by the surgical plan and/or planned trajectory as determined by the controller or surgeon. It may be noted that in this optimal implementation of the disclosed system, insertion opening incision 11 is limited only by the size of cannula 12 itself.

Referring now to fig. 3B, wherein the angle of cannula 12 is adjusted by the surgical robot as bio-ink is expressed from nozzle 2 for forming first layer 30 of bio-ink in the subject. As previously mentioned, the multiple degrees of freedom provided by the surgical robot allow for maintenance of the insertion point as a fulcrum. It can be seen in this figure how cannula 12 is maneuvered around a single insertion point 11 without stressing, tearing or expanding the opening. By programming the robot to coordinate the linear movement of the cannula and its angular movement, it is possible to print a rectilinear layer or even any other line shape.

Referring now to fig. 3C, cannula 12 is shown being withdrawn longitudinally to a position where a second layer 31 of bio-ink is to be formed, the second layer 31 being adjacent to first layer 30. As the bio-ink is controllably ejected, the angle of cannula 12 is swept by the robot to a new longitudinal position, forming a second layer 31 of bio-ink. Although a gap is shown between first layer 30 and second layer 31 in the figures, it is to be understood that each bio-ink layer is formed in contact with substantially the previous layer so that planar tissue element 10 may be formed. This process is repeated with cannula 12 being withdrawn further and with more layers being formed until the first transverse layer has been completed according to the surgical plan and/or planned trajectory.

In order to build a true three-dimensional printing element, it is now necessary to print an additional biological layer on top of the first tissue layer. Reference is now made to fig. 3D, which shows how cannula 12 is adjusted to continue printing a new lateral level so that a new layer 32 can be formed within the next lateral level. This process is shown in fig. 3B and 3C, and then repeated at a new lateral level. Even within a single layer, different types of cells may be used. After the cannula has reached all the required lateral levels and the required layers have been formed at each lateral level, the three-dimensional tissue element is completed and the cannula can be completely withdrawn from the subject.

Figures 3A to 3D illustrate the formation of layers in which the cannula performs movement in a manner substantially parallel to the layer being printed. This configuration is useful in the generation of layers in locations with limited headroom (headroom). However, it is also possible and often simpler to perform the movement to print the layer when the cannula is substantially perpendicular to the layer being printed, as the anatomical geometry allows.

Referring now to fig. 4A-4D, an exemplary motion pattern of robotically controlled cannula 12 is shown, the robotically controlled cannula 12 being inserted vertically according to fig. 1, using insertion point 11 in skin 22 of a subject as a fulcrum to form layers of bio-ink.

Referring now to fig. 4A, there is shown cannula 12 inserted generally perpendicularly through a minimally invasive incision 11 in the subject's skin 22 toward a target 3D printing area (not shown). The working space 40 (which is the potential volume of layers in which tissue may be formed by the surgical robot) is shown as a cone, which is the largest working space volume that may result from a single fulcrum. As in the implementation of fig. 3A to 3D, the insertion opening 11 should be limited only by the size of the cannula 12 itself.

Referring now to fig. 4B, it is shown that cannula 12 is oriented about incision 11 as a fulcrum, while bio-ink is ejected from nozzle 2 to form a first lateral layer 41 of bio-ink within the subject, which first lateral layer 41 is typically the deepest layer. Layer 41 in this figure is shown as circular, but may be of any shape depending on the surgical plan and/or planned trajectory. As previously mentioned, the multiple degrees of freedom of the surgical robot (shown in fig. 1) allow for maintenance of the insertion point 11 as a fulcrum. It can be seen in this figure how cannula 12 is maneuvered around a single insertion point 11 without stressing, tearing or expanding opening 11.

Referring now to fig. 4C, cannula 12 is shown being robotically withdrawn a predetermined amount through incision 11 using a robotic activation arm (activation arm) to prepare second layer 42 of bio-ink to be formed. As the bio-ink is controllably ejected from the nozzle 2, the angle of the cannula 12 is adjusted by the robot into a new longitudinal position, thereby forming a second layer 42 of bio-ink. Although shown in the figures as there being a gap between first layer 41 and second layer 42, it is to be understood that each bio-ink layer is formed in substantial contact with the previous layer so that three-dimensional tissue element 10 may be formed. This process is repeated with cannula 12 being withdrawn further incrementally and with more layers being formed until the shallowest layer has been completed according to the surgical plan and/or planned trajectory.

Referring now to fig. 4D, a fully formed three-dimensional tissue element 10 is shown. Since the 3D printing process has been completed, cannula 12 is completely withdrawn from the subject through incision 11 in skin surface 22 in a manner that does not increase the size of incision 11.

Since the techniques shown in fig. 3A-3D and 4A-4D minimize trauma, in some cases, performing the surgical procedure in stages, it may be advantageous to build up subsequent layers after the previous layers have healed (heal) thereby enhancing the structural rigidity of the printed volume.

Referring now to fig. 5, an exemplary application of the robotic surgical system of the present disclosure is shown that is used to form three-dimensional cartilage elements in situ within a subject's knee, generally reinforcing and strengthening the cartilage remaining in the joint. This application shows in particular the advantages of the present system, since the limited space available will make it very difficult to insert the prefabricated cartilage element into the knee joint and its probability of acceptance is lower than that of an element deposited in situ within the joint. The fabrication of knee cartilage is performed through a lateral minimally invasive incision 11, which minimally invasive incision 11 can be as small as 1mm. Because the space available for this application is very limited, cannula 12 uses a fine needle for ejecting the bio-ink to the area to be applied, with one or more bio-inks stored in a syringe-like cylinder adjacent the needle cannula for ejection. Needle cannula 12 is shown passing under patella 50, over medial meniscus 51, and the surface of anterior cruciate ligament 54, and into articular cartilage 53 of the knee (the point of application is hidden under the medial condyle), where bio-ink will be ejected from the nozzle of the cannula (shown in fig. 1) to form a three-dimensional cartilage element. Femur 55 and tibia 52 are also shown. Manipulation of cannula 12 is controlled by surgical robot 1 in accordance with instructions provided by a controller. Coordinated movement of the robotic joints allows the insertion point 11 to be maintained as a fulcrum of movement throughout the surgical procedure. Because of the compact space available, the surgical procedure may require the application of external traction devices. Referring now to fig. 6A and 6B, an overview of an exemplary configuration for a process performed by a controller of a robotic surgical system of the present disclosure is shown, along with inputs thereto and outputs therefrom. Fig. 6A shows a simple configuration for the controller 21, where the inputs may be a planned cannula nozzle trajectory at input 61 and an injection routine associated with the trajectory at input 62. The input information may be determined by the surgeon based on the needs of the subject as diagnosed from the pre-operative image. Based on his/her experience, and based on analysis of the pre-operative image, the surgeon can plan the shape, size, composition, and location of the desired bioprinted element or organ. In this first configuration, the output from the controller 21 will be a set of instructions 65 issued to the robotic system for executing the planned trajectory of the surgeon, and an associated set of instructions 66 issued to the bio-ink robotic ejector mechanism for executing the plan of bio-ink ejectors 66 for coordinating with the robotic trajectory of the cannula nozzle, for generating the elements of the planned print of the surgeon.

Fig. 6B shows a second and higher level configuration of the controller 21, wherein the input may be a surgical plan 63, the surgical plan 63 defining a predetermined shape, composition, location and size of the three-dimensional tissue element to be printed. Alternatively, the pre-operative image of the area to be treated may be a direct input 64 to a controller configured to perform an analysis thereof to determine an acceptable or optimal surgical plan, which may include the use of artificial intelligence, including accessing the medical database 60 and extracting information therefrom. Such analysis may include, among other things, analysis of preoperative images for determining the extent of tissue damage, diagnosis of subject-based medical profiles, knowledge from similar case databases (including 3D printed surgical procedures performed on the area), and the results thereof, as well as any other clinically relevant factors. The surgical plan may be selected by the controller based on a number of other factors, such as, for example, a need to avoid forbidden areas where the cannula may be damaged, the type or density of tissue at the target site, the shape of anatomical features at the target site, size limitations of three-dimensional tissue elements due to constrained anatomical boundaries, and location or size limitations intended to reduce trauma to tissue of the subject. In addition to the input 64 for the determination of the surgical plan and the analysis of the pre-operative images, the controller may use such pre-operative images of the subject for image registration purposes. Such images may be registered with intraoperatively obtained data (such as input 67 to the controller from a reference marker or fluoroscopic imaged anatomical element) to allow the controller to determine the intraoperative position of the surgical robot relative to the subject and also relative to the surgical plan obtained from the preoperative image, and instruct the surgical robot to the appropriate pose accordingly.

According to a further proposed aspect of the system implementation, the controller may be configured for comparing the preoperative 3D image 64 of the region of interest of the subject with a preoperative 3D image (as obtained from the database 60) expected from a healthy person having a medical profile similar to the medical profile of the subject, such that the controller may determine an optimal shape, size and/or location of the volume of tissue to be implanted in order to bring the region of interest of the subject back to the characteristics of the healthy person. Finite element or voxel analysis may be performed on the equivalent volume in the image of the healthy person mentioned above, and the level of gray units of that volume may be converted into a corresponding bio-ink material (which will provide the correct density at each location) for creating a bio-ink map that will be part of the surgical plan. Alternatively or additionally, the shape, volume, or location of tissue for a surgical plan may be determined from analysis of patients with similar diagnoses or injuries (e.g., cartilage injuries), and then the plan may be calculated based on the highest statistical likelihood of positive outcome. By determining whatever way the surgical plan is, parameters generated from the preoperative plan may be stored in the controller for positioning the robot and for coordinating the ejection of the bio-ink during the surgical procedure.

The output from the controller 21 shown in fig. 6B is a planned trajectory 68 and a plan 69 for jetting, which will be performed after the surgical plan is processed. The planned trajectory should be the most efficient or optimal trajectory and may be modified by considering (i) avoiding forbidden areas that would be damaged by the cannula; (ii) forming a shortest track of the three-dimensional tissue element; and (iii) calculating at least one of the trajectories that will cause minimal trauma to healthy tissue of the subject. The schedule for the bio-ink ejection may include the speed of the bio-ink extrusion mechanism (such as piston movement), the time elapsed for the bio-ink ejection, and/or the metered amount of bio-ink to be extruded. The planned flow rates and planned trajectories should be determined such that they can operate jointly to allow the surgical robot to autonomously complete the surgical plan. The controller may also use the planned trajectory and the planned jetting to determine predetermined amounts, compositions, and sequences of layers of bio-ink required to preoperatively prepare the cannula according to the surgical plan. The controller may select a type of bio-ink that is optimal for the surgical procedure from a range of possible bio-inks. Additionally, if the surgeon otherwise determines, he/she may override the selection of the (override) system and may replace the substitute bio-ink into the surgical plan for recalculating the optimal output.

Referring now to fig. 7, there is a flow chart illustrating one exemplary method of planning a robotic three-dimensional bioprinting surgical procedure using the controller 21. In step 70, a 3-dimensional image set of the subject is obtained, such as derived from MRI, CT or ultrasound images, and stored for use in registration of a surgical robot for a 3D bioprinting surgical procedure. In step 71, the preoperative 3-dimensional image set is used to determine a surgical plan including the shape, composition, location, and size of the 3-dimensional tissue elements to be formed within the subject. The controller then converts the surgical plan into a set of operating characteristics including the type, shape, and size of layers to be printed, the correct position of the three-dimensional object relative to the anatomy of the subject, and the correct bio-ink assembly for each position within the shape. As one non-limiting example, a user may electronically locate and insert dots representing different types of bio-ink onto a virtual pre-operative image to create a desired three-dimensional shape.

In step 72, the surgical plan is processed, typically by using CAD-based software, to generate a file representing the surgical plan that is readable by the controller.

In step 73, the file is processed using the controller to determine (a) a planned trajectory for the nozzles of the surgical robot, and (b) a planned trajectory for the ejection of the one or more bio-inks, the planned trajectory and the planned for the ejection being stored to instruct the surgical robot and the ejection mechanism during the surgical procedure. The planned trajectory and the plan for jetting may together be considered a surgical plan, including the required robot printer movements to achieve the desired trajectory in multiple degrees of freedom, as well as the required positions and types of bio-ink jetting during the movements. Thus, it is possible to determine with a high level of accuracy which movements the robotic arm of the surgical robot will require to enable both the planned trajectory and the maintenance of the pivot point. Similarly, the movement or actuation of the extrusion mechanism may also be determined, such as the exact desired speed of the piston required during the entire surgical procedure.

The planned trajectory and the plan for injection may be determined as described above with respect to fig. 6B. In step 74, using an example of a method performed with a surgical system having a small diameter cannula for carrying a single cylindrical volume of bio-ink, the amount, location, and composition required for each longitudinally stacked layer of bio-ink is determined from the determined planned trajectory and the plan for jetting. In alternative methods of the invention, such as if only one type or composition of bio-ink is required, or if the cannula is divided into separate chambers adapted to carry different bio-ink types, the separate chambers are independently activated, this step 74 may not be required.

Referring now to FIG. 8, an exemplary method is shown depicting the actual steps as follows: the robot 3 vitamin printing procedure generated using the controller 21 is performed to also perform registration of the intra-operatively acquired images with the pre-operative plan and registration of the coordination system of the robot with the coordination system of the pre-operative images. Although the steps shown in fig. 8 include a comprehensive surgical procedure, it is to be understood that not all steps are generated by the controller in essence, but that some steps may be performed or entered by externally determined steps or by surgeon intervention.

In step 80, the coordination system of the surgical robot is registered with the surgical plan using the preoperative 3D image set. In step 81, an insertion point is positioned on the subject, the insertion point being derived from the planned trajectory, and the surgical robot is commanded to the appropriate pose for entry. In step 82, a minimally invasive surgical incision is created in the subject, and the surgical robot is instructed to insert a small diameter cannula at a predetermined angle as determined by the surgical plan at the insertion point of the subject. Since the printhead does not include imaging elements that would increase its size, the surgical procedure can be performed in a minimally invasive manner through a small opening (e.g., 1 mm). This greatly reduces trauma to surrounding tissue and reduces recovery time for the subject.

Once the cannula reaches the desired depth of penetration according to the planned trajectory, a first layer of bio-ink is controllably jetted by the extrusion mechanism in coordination with the movement of the cannula (as controlled by the surgical robot) in step 83. As shown in fig. 3A-3D and fig. 4A-4D, the subject's insertion point should be maintained as a pivot point throughout this process. The first layer of bio-ink is ejected by instructing the surgical robot to the correct shape, composition, position relative to the subject and size according to the planned trajectory and the plan for ejecting.

After the bio-ink layer has been formed, it is determined whether the required 3-dimensional tissue elements have been completely generated in step 85. If not, the system instructs the cannula to longitudinally withdraw a predetermined incremental amount in step 85 and adjusts the angle of the cannula according to the planned trajectory to form a second layer of bio-ink. Step 85 is described as a lateral surgical procedure described in fig. 3A-3D. The required movements for the execution of the surgical procedure of fig. 4A to 4D should be modified accordingly. The system then again checks whether the required 3-dimensional organization elements have been completely generated in step 86. If not, the system instructions repeat this step 85. If the 3-dimensional tissue element has been completed, the surgical procedure may end (as in step 86) and the cannula may be completely withdrawn from the subject. If additional incisions are needed to achieve the desired size and shape of the three-dimensional object, steps 81 through 87 may be repeated during the same surgical procedure or during another surgical procedure on a later date.

The method of fig. 8 is typically performed autonomously by the controller and the surgical robot; however, the controller may receive optional user input, such as if the surgeon wishes to interrupt the surgical procedure or override a predetermined surgical plan. If desired, the practitioner may alter the planned surgical robotic printer motion, or alter the location and type of bio-ink ejection during that motion. For example, the planned trajectory may be based on an efficiency algorithm and may be a trajectory for a single surgical procedure, but the surgeon may decide to divide the surgical gauge into two surgical procedures, build a subsequent layer after the previous layer has healed, thereby enhancing the structural rigidity of the printed volume.

In summary, the systems and methods of the present disclosure provide high precision, low trauma, small incision size, minimal radiation exposure, and less chance of infection than might be encountered in an in vitro biological element printing surgical procedure (after which the element is inserted through a more aggressive surgical procedure).

It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. On the contrary, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not in the prior art.

Claims

1. A system for forming a three-dimensional tissue element in a subject, the system comprising:

a cannula (12), the cannula (12) being configured for insertion into the subject through a surface opening (11), the surface opening (11) having a lateral dimension substantially similar to a lateral dimension of the cannula, a proximal end of the cannula being configured for attachment to a surgical robot (1) and a distal end comprising a nozzle (2), the nozzle (2) being adapted for jetting one or more bio-inks to form at least one layer of bio-material in the subject;

at least one bio-ink extrusion mechanism (15), the at least one bio-ink extrusion mechanism (15) configured for ejecting the one or more bio-inks from the distal end of the cannula; and

-a controller (21), the controller (21) being adapted for:

(i) Instructing the surgical robot to adjust a longitudinal position and orientation of the cannula within the subject according to a preoperative surgical plan based on at least a three-dimensional preoperative image set; and

(ii) Controlling the extrusion mechanism (15) such that the bio-ink is ejected in dependence of the longitudinal position and the orientation of the cannula in the subject,

Wherein the surgical robot is configured for performing the adjustment of the orientation of the cannula within the subject using the surface opening as a pivot point for the orientation of the cannula such that a three-dimensional tissue element having a size greater than the lateral dimension of the cannula can be formed within the subject; wherein the system further comprises at least one three-dimensional tracking target (18) associated with the surgical robot, and wherein the controller is adapted for registering a coordinate system of the surgical robot to the three-dimensional preoperative set of images using the at least one three-dimensional tracking target (18); and is also provided with

Wherein the system further comprises image data of a reference marker (18) or a fluoroscopic imaged anatomical element provided on at least one anatomical element of the subject, and wherein the controller is further adapted for registering a coordinate system of the surgical robot to the reference marker (18) or the fluoroscopic imaged anatomical element using the at least one three-dimensional tracking target; and wherein the controller is further adapted for: creating a pseudo-three-dimensional image, and associating, by an image processing method, a selected window of the pseudo-three-dimensional image with a similarly selected window of the set of three-dimensional preoperative images such that the position of the surgical robot can be registered using the preoperative surgical plan, the pseudo-three-dimensional image being an image having the position of the surgical robot identified therein, the coordinate system of the surgical robot including anatomical elements imaged with respect to the anatomical reference markers or fluorescence; and is also provided with

Wherein the one or more bio-inks (25) are contained in (i) the cannula or (ii) one or more bio-ink storage volumes in fluid connection with the cannula, and preferably wherein the cannula is configured for containing at least two bio-inks arranged in layers along a length of the cannula, the layers having a predetermined amount, composition and order.

2. The system of claim 1, wherein the preoperative surgical plan comprises at least (i) a geometric form, (ii) a composition, (iii) a location, and (iv) a size of the three-dimensional tissue element.

3. The system of any one of the preceding claims, wherein the preoperative surgical plan is determined using at least one of: (i) Image processing of the three-dimensional preoperative image set, (ii) input from a surgeon, and preferably wherein the determination of the preoperative surgical plan further utilizes analysis of data from a medical database (60).

4. The system according to any one of the preceding claims, wherein the one or more bio-inks (25) are contained in: (i) In the cannula or (ii) in one or more bio-ink storage volumes in fluid connection with the cannula, and preferably wherein the cannula is configured for containing at least two bio-inks arranged in layers along the length of the cannula, the layers having a predetermined amount, composition and order.

5. The system of claim 4, wherein the cannula is configured to contain at least two bio-inks arranged in layers along a length of the cannula, the layers having predetermined amounts, compositions, and orders, and wherein the predetermined amounts, compositions, and orders of the layers are determined by the controller according to the preoperative surgical plan.

6. The system according to any of the preceding claims, wherein the controller is adapted for forming the three-dimensional tissue element by: (a) Performing an adjustment of the orientation of the cannula at a first depth in conjunction with the incremental longitudinal movement of the cannula to form a first layer of biological material, and (b) subsequently moving the cannula to a second depth within the subject, and performing an adjustment of the orientation of the cannula at the second depth in conjunction with the incremental longitudinal movement of the cannula to form a second layer of biological material, and repeating (b) until the three-dimensional tissue element is formed.

7. The system according to any of the preceding claims, wherein the surface opening (11) is adapted for providing access to the subject's knee joint.

8. The system according to any of the preceding claims, wherein the bio-ink extrusion mechanism is any of a piston (15), an external pressure application device, a pneumatic device or a bio-ink jet printhead.

9. The system of any one of the preceding claims, wherein the cannula is less than 1mm in diameter, or wherein the cannula is less than 3mm in diameter.

10. The system of any one of the preceding claims, further comprising a steering mechanism for steering the nozzle of the cannula to a desired direction, and/or wherein the cannula comprises at least one controlled link or joint such that the nozzle has increased accessibility.